RRC ID 61651
Author Niikura K, Nakajima S, Takano M, Yamazaki H.
Title FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats.
Journal Bone
Abstract There is considerable evidence that osteoclasts are involved in the pathogenesis of juxta-articular bone destruction in rheumatoid arthritis. Vacuolar ATPases (V-ATPases), which are highly expressed in the ruffled border membrane of osteoclasts, play a central role in the process of bone resorption, and V-ATPase inhibitors are effective in preventing bone destruction in several animal models of lytic bone diseases. Here, we evaluated for the first time the effects of V-ATPase inhibition in rats with adjuvant-induced arthritis (AIA) using FR177995, a novel V-ATPase inhibitor. FR177995 completely inhibited H(+) transport driven by V-ATPase, but exerted no effect on the H(+) transport activities of F- and P-ATPase, indicating that FR177995 is a specific inhibitor of V-ATPase. FR177995 acted directly on osteoclastic bone resorption and equally inhibited in vitro bone resorption stimulated by IL-1, IL-6 or PTH. In addition, FR177995 dose-dependently reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats. When FR177995 was administered to AIA rats once a day, the loss of femoral bone mineral density was significantly improved. Moreover, indicators of cartilage damage (arthritis score and glycosaminoglycan content in the femoral condyles) and inflammation parameters (paw swelling volume, erythrocyte sedimentation rate and plasma sialic acid level) were found to be unexpectedly ameliorated. These results strongly suggest that V-ATPase may be an interesting drug target in the treatment of rheumatoid arthritis.
Volume 40(4)
Pages 888-94
Published 2007-4-1
DOI 10.1016/j.bone.2006.10.015
PII S8756-3282(06)00795-2
PMID 17157574
MeSH Animals Arthritis, Experimental / drug therapy* Arthritis, Experimental / immunology Arthritis, Experimental / pathology Autoimmunity / drug effects Benzimidazoles / chemistry Benzimidazoles / pharmacology* Bone Density / drug effects Bone Resorption / prevention & control Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Female Hypercalcemia / drug therapy In Vitro Techniques Inflammation / prevention & control Male Mice Morpholines / chemistry Morpholines / pharmacology* Pregnancy Rabbits Rats Rats, Inbred Lew Rats, Wistar Vacuolar Proton-Translocating ATPases / antagonists & inhibitors* Vacuolar Proton-Translocating ATPases / immunology
IF 4.147
Human and Animal Cells ST2(RCB0224)